Interaction between electrical modulation of the brain and pharmacotherapy to control...

Pharmacology & Therapeutics 138 (2013) 211–228

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Pharmacology & Therapeutics

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Interaction between electrical modulation of the brain and pharmacotherapy tocontrol pharmacoresistant epilepsy

Luisa Rocha ⁎Pharmacobiology Department, Center for Research and Advanced Studies, Calz. Tenorios 235, Col. Granjas Coapa, Mexico City 14330, Mexico

Abbreviations: AED, Antiepileptic Drug; AMPA, α-aBrain-Derived Neurotrophic Factor; Ca2+, Calcium; DBHFS, High Frequency Stimulation; LTP, Long-term PotenNa+, Sodium; STN, Subthalamic Nucleus; TLE, TemporaNerve Stimulation; VDCCs, Voltage-Dependent Ca2+ Ch⁎ Tel.: +52 55 54 83 28 59; fax: +52 55 54 83 28 63

E-mail address: [email protected].

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a b s t r a c t
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Keywords:
PharmacoresistanceEpilepsyDeep Brain StimulationTranscranial Magnetic StimulationVagal Nerve Stimulation
In spite of the high success rate of many surgical procedures for pharmacoresistant epilepsy, a substantial num-ber of patients do not become seizure-free. Different strategies for electricalmodulation of the brain such asDeepBrain Stimulation, Vagal Nerve Stimulation and Transcraneal Magnetic Stimulation have gained considerable in-terest in the last decade as alternative therapies for patients withmedically refractory epilepsy. Research into themechanism of action of the strategies for electrical modulation of the brain suggests a crucial role of differentmolecules and channels such as glutamate, γ-aminobutyric acid, adenosine, brain-derived neurotrophic factor,calcium channels, sodium channels as well as extracellular potassium. Electrical modulation of the brainmay re-duce the overexpression of P-glycoprotein, a drug efflux transporter that reduces the absorption of antiepilepticdrugs. Electrical modulation of the brain induces long-term effects associated with beneficial consequences onclinical symptoms observed during the postictal state. In addition, electrical modulation of the brain mightalso promote the neurogenesis in subjects with pharmacoresistant epilepsy in whom this process is decreased.Targeting the regulatory pathways in charge of the effects of electrical modulation of the brain is discussed asa means to improve its efficacy. Electrical modulation of the brain combined with pharmacotherapy mayrepresent an innovative approach to avoid epileptogenesis, reduce seizure activity, induce beneficial effects dur-ing the postictal state, diminish the amount of antiepileptic drugs, and improve alertness, memory and mood inpharmacoresistant epilepsy.

© 2013 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2112. Electrical modulation of the brain in epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2123. Electrical modulation of the brain and pharmacotherapy: current evidence and future potential to control

pharmacoresistant epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2124. Relevance of long lasting effects induced by electrical modulation of the brain . . . . . . . . . . . . . . . 2145. Neurogenesis and electrical modulation of the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . 2146. Role of inherent severity of epilepsy and brain damage on the effects induced by electrical modulation of the brain . 2167. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217222

mino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATP, Adenosine-5′-triphosphate; BBB, Blood Brain Barrier; BDNF,S, Deep Brain Stimulation; EEG, Electroencephalographic; [K+]o, Extracellular Potassium; GABA, γ-Aminobutyric Acid;tiation; NMDA, N-Methyl-D-aspartic acid; NTS, Nucleus of the Solitary Tract; PD, Parkinson Disease; Pgp, P-glycoprotein;l Lobe Epilepsy; TMS, Transcranial Magnetic Stimulation; rTMS, Repetitive Transcranial Magnetic Stimulation; VNS, Vagalannels..

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212 L. Rocha / Pharmacology & Therapeutics 138 (2013) 211–228

1. Introduction

Epilepsy is a chronic, recurrent, frequently progressive neurologicaldisorder that affects 1–2% of the population worldwide. It is character-ized by abnormal synchronization of neural activity. Pharmacotherapyis the treatment of choice for control of epileptic seizures and the selec-tion of antiepileptic drugs (AEDs) depends on several factors such as thetype of epilepsy and drug tolerability (Browne & Holmes, 2001).

Though the majority of patients respond to treatment with AEDsadequately, about one third of them experience pharmacologicallyresistant epilepsy, which is generally defined as the failure of seizuresto come under complete control or acceptable control in response toAED therapy (Berg, 2009). Clinical characteristics associated withresistance include early onset of epileptic seizures (before one yearof age), elevated seizure frequency before onset of treatment, historyof febrile convulsive seizures, brain lesions, malformations of corticaldevelopment and dysembryoplastic neuroepithelial tumors (Semahet al., 1998; Regesta & Tanganelli, 1999; Sisodiya et al., 2002;Rogawski & Johnson, 2008).

A high level of excitatory neurotransmission could be a neurobi-ological factor that may underlie augmented susceptibility to developpharmacoresistance (Arroyo et al., 2002; Rogawski & Johnson, 2008;Luna-Munguia et al., 2011). At the cellular level, intractability ofepilepsy is associated with factors such as abnormal reorganization ofneuronal circuitry, alteration in several neurotransmitter receptors,canalopathies, reactive autoimmunity as well as the abnormal inade-quate penetration of AEDs into the epileptic focus due to changes inthe blood brain barrier (BBB) (Vreugdenhil & Wadman, 1999; Kwan &Brodie, 2002; Ellerkmann et al., 2003; Remy et al., 2003). Other factors,such as the cell junctions in the vascular endothelium and astrocytes,which undergo important changes as a consequence of repetitiveepileptic seizures (Kasantikul et al., 1983; Lamas et al., 2002), mayalso play a role in pharmacoresistance.

Epilepsy is considered an important public health problemwith sig-nificant social and economic impact (Engel & Taylor, 1997). It is estimat-ed that about 37 million individuals in theworld have primary epilepsy,a number that increases to approximately 50 million when epilepsysecondary to other diseases or injuries is considered (World HealthOrganization, 2001). Interestingly, it is calculated that at least 100 mil-lion people will have epilepsy at some time in their lives (Reynolds,2002). In developed countries, the incidence of epilepsy is remarkablyconsistent across geographical areas, ranging from 24 to 53 per100,000 person-year (Kurland, 1959; Keränen et al., 1989; Olafsson etal., 1996), whereas the prevalence ranges from 3.5 to 10.7 (de Graaf,1974; Haerer et al., 1986). In contrast, epidemiological studies indicatehigher prevalence and incidence rates of epilepsy in the general popu-lation of developing countries. For example, in Latin America, the medi-an lifetime prevalence in all countries is 17.8 (range 6–43.2) per 1000people, and the incidence is 77.7–190 per 100,000 people per year(Burneo et al., 2005). Developing countries manifest more than 80% ofpersons with epilepsy, a situation associated with a lack of appropriatetreatment (Carpio & Hauser, 2009).

The burden of epilepsy is high and, for the year 2000, accounted forapproximately 0.5% of the whole burden of diseases in the world(World Health Organization, 2001; Leonardi & Ustun, 2002). Patientswith epilepsy have significantly higher rates of health-related contactsand medication use as well as a higher socioeconomic cost, loweremployment rates and income. Socioeconomic impact of epilepsy hasbeen evaluated in different countries. In the U.K. 400,000 people haveactive epilepsy and represent a cost of £600 million annually in directcare and £2 billion annually in overall cost to the nation (Bowis,2002). A Danish study indicates that the direct net annual health careand indirect costs are €14,575 for patients in contrast with €1163 forpeople without epilepsy, giving a consequent excess cost of €13,412(Jennum et al., 2011). In the U.S., the direct medical costs for patientswith no seizures during the previous year was $US 251, for patients

with less-than one-seizure-per-month $US 1333, and $US 2439 for pa-tients presenting more than one seizure per month (Annegers et al.,1999; Platt & Sperling, 2002). In Mexico, a study published in 2006revealed that themean annual healthcare cost per patientwith epilepsywas $US 2646 (García-Contreras et al., 2006). It is important to notethat, according to multinational studies, costs of healthcare for patientswith pharmacoresistant epilepsy are higher than those for non-refractory epilepsy patients (Begley & Beghi, 2002).

In addition to the economic burden, epilepsy may have a substan-tial social impact because people with this disorder and their familiesall over the world experience prejudice and discrimination, isolationand exclusion. People with epilepsy are victims of society's stigmaand live their life on the margins of society (Lee, 2002). This situationis worse for patients who experience pharmacoresistant epilepsy(Regesta & Tanganelli, 1999).

In carefully selected cases of pharmacoresistant epilepsy, surgical re-moval of the epileptogenic zone is superior to continued medical treat-ment in completely controlling seizures and improving health-relatedquality of life (Wiebe et al., 2001). After epilepsy surgery, total costsfor seizure-free patients decline by 32% at a 2-year surgical follow-updue to decreased use of AEDs and inpatient care needs. In the 18 to24 months following evaluation, epilepsy-related costs are $US 2094in patients with persisting seizures vs. $US 582 in seizure-free patients(Langfitt et al., 2007).

In spite of the high economical burden that pharmacoresistant ep-ilepsy represents, it is important to consider that not all patients withthis disorder are candidates for resective epilepsy surgery. Thus, thereis a great need to develop other therapeutic strategies to control sei-zure activity for those patients who do not respond to AEDs.

Neuroscientists have long attempted to apply external electricalstimulation to modulate brain function. Electrical modulation of thebrain or neuromodulation has evolved from the early application of tor-pedo fish to the stimulation of superficial or deep brain structures, var-ious nerves in the central nervous system, peripheral nervous systemorautonomic nervous system. Neuromodulation strategies are focused onrestoring the balance of circuits that are disrupted as consequence of avariety of neurologic and psychiatric disorders, many of which are notadequately controlled by medical therapy.

2. Electrical modulation of the brain in epilepsy

2.1. Deep Brain Stimulation

During the 20th century, the rationale for applying electrical stimu-lation in specific brain structures was supported by studies carriedout in experimental models and humans. Concerning animal models,Rosenblueth and Cannon (1942) found that cortical stimulation incats at high frequencies (40 Hz) induced inhibitory effects on epilepti-form activity, whereas slow frequencies (0.5–2 Hz) produced activationfollowed by prolonged depression. These authors also reported thattonic–clonic electrographic components were not elicited in spite ofhigh frequency electrical stimulation applied for prolonged periods.Cooke and Snider (1953) demonstrated that cerebellar stimulationmaymodify the electrographic pattern of seizure activity and, eventual-ly, may arrest it. Dow et al. (1962) reported that cerebellar electricalstimulation reduced focal seizure activity induced by local applicationof cobalt on the brain, but it was unable to inhibit generalized seizures.

In 1941, Penfield and Erickson provided the first evidence for theassociation of electrical brain stimulation and epilepsy in humans(Penfield & Erickson, 1941). These authors found that electrical stimula-tion of the occipital cortex reproduced elementary visual hallucinationsassociated with occipital lobe epilepsy. Thereafter, cortical stimulationwas used to evoke epileptiform activity and identify the epilepticfocus (Penfield & Kristiansen, 1951; Penfield & Jasper, 1954). The firstindication that application of electrical stimulation to control seizure ac-tivity in patients with pharmacoresistant epilepsy was reported by

213L. Rocha / Pharmacology & Therapeutics 138 (2013) 211–228

Cooper et al. in the early 1970s. Although these authors were interestedin reducing cerebral palsy and spasticity by electrical stimulation, theyfound that cerebellar stimulation reduced seizure activity in 11of 15 pa-tients with intractable epilepsy. Their results led to the suggestion thatcerebellar stimulation induces inhibitory effects through activation ofPurkinje neurons with a subsequent reduction of cerebral activity(Cooper, 1973; Cooper et al., 1973). Although the results obtained byCooper's groupwere excellent, the application of cerebellar stimulationwas stopped because subsequent trials failed to show efficacy (Schwalb& Hamani, 2008). In 1980, Cooper and collaborators evaluated the ef-fects of Deep Brain Stimulation (DBS) for the first time. They foundthat electrical stimulation of the thalamus and internal capsule pro-duced improvement in pain, hemiparesis, dystonia, torticollis, tremor,speech impairment and epilepsy (Cooper et al., 1980). At present, DBShas evolved significantly and different approaches exist to reduce oravoid epileptic activity.

DBS using high frequency stimulation (HFS) at 130 Hz is nowwidelyused to alleviate bradykinesia and muscular rigidity in patients withParkinson's disease (PD). In 1987, Benabid et al. provided the first obser-vation that HFS at 130 Hz was able to reduce essential tremor andextra-pyramidal dyskinesias. These authors reported thatHFS of the ven-tral intermediate nucleus reduces PD tremor, an effect lasting from 2 to14 months. At present, several brain targets for HFS show some degreeof success in patients with epilepsy: thalamus (centromedian nucleusand anterior thalamus) (Velasco et al., 1987, 2001; Lim et al., 2007;Franzini et al., 2008), subthalamic nucleus (STN) (Chabardès et al.,2002), amygdala and hippocampus (Velasco et al., 2001; Vonck et al.,2002), among others.

Concerning characteristics of electrical stimulation, studies supportthe notion that the optimal waveform for DBS is a waveform otherthan the perfect square (Merrill et al., 2005; Foutz & McIntyre, 2010).For example, Lilly wave pulses, a type of electrical waveforms that canbe applied for several months without causing detectable injury andsignificant changes in threshold (Lilly, 1961), have been effectivelyused to apply HFS in patients with pharmacoresistant epilepsy(Velasco et al., 2000). Another relevant issue is that the effects of theelectrical fields depend on their orientation in relation to neurons(Patel & Poo, 1982). Regarding stimulus polarity, cathodic stimuli resultin lower thresholds for electrodepositions over the axonwhereas anod-ic stimuli result in lower thresholds for electrode positions over the cellbody and dendrites (McIntyre & Grill, 1999).

Experiments have been conducted to evaluate the timing of stimu-lus delivery, namely open loop (delivered on a scheduled basis and in-dependent of epileptiform activity) and closed-loop (triggered by ictalactivity). Open loop has been found to be effective in non-focal epilepsy(Zumsteg et al., 2006), whereas closed loop is effective in focal andnon-focal epilepsies. The rate of stimulation, current intensity, stimulusduration, stimulus waveform and location of electrodes are parametersthat may influence the response to both open and closed loop stimula-tion (Skarpaas & Morrell, 2009).

Suppression of somatic neuronal activity (Beurrier et al., 2001; Lian etal., 2003), synaptic depression of excitatory neurotransmission (Schiller& Bankirer, 2007) and blockage of axonal conduction (Jensen &Durand, 2009), are somemechanisms that can account for the enhancedseizure threshold induced by HFS. Spontaneous firing activity of neuronshas been proposed to be blocked after HFS as a result of a strong depres-sion of intrinsic sodium (Na+) and calcium (Ca2+) voltage-gatedcurrents underlying single-spike and bursting modes of discharge(Beurrier et al., 2001). Other studies indicate that HFS may involve re-lease of neurotransmitters rather than primary electrogenic inhibitionof neurons (Lee et al., 2004). Experimental evidence suggests that HFSreplaces the preexisting deleterious activity by spikes, time-locked tothe stimuli and thus presenting a striking regularity (Garcia et al., 2003,2005). HFS has been proposed to induce depolarization blockage pro-duced when action potentials cannot be initiated as a consequence ofpersistent membrane depolarization resulting from tonic inactivation

of Na+ channels (Hille, 1992), and is associatedwith tonic increase in ex-tracellular potassium ([K+]o) (Bickson et al., 2001).

Another theory is that HFS-induced effects are equivalent to lesions,a notion supported because stimulation induces a functional inhibitionmimicking the effects of ablative surgery (Benabid et al., 1987, 1991,2005). At the cell body level, HFS inhibits neuronal firing (Dostrovsky& Lozano, 2002; Filali et al., 2004). However, at the feedback level ofaxons originating from stimulated neurons, HFS might excite these ele-ments, but the propagated spikes are ineffective at the synaptic level(McIntyre et al., 2004). This situation results in decoupled activity inthe axon and cell body of stimulated neurons (Gubellini et al., 2009).In addition, axons impinging upon stimulated neurons and their termi-nals would be excited and would deliver their neurotransmitters(Gradinaru et al., 2009), but their effect would be inefficient due to in-hibition of spike initiation by HFS (Benabid et al., 2005).

Concerning neurotransmitter release, HFS induces a transientrelease of glutamate under normal conditions (Lee et al., 2007; Luna-Munguía et al., 2012), probably as a consequence of continuous celldepolarization until “depolarization block” occurs (Poolos et al., 1987;Bickson et al., 2001). The initial enhancement of glutamate releasemay correspond to HFS-induced activation of glutamatergic fibersand/or cells that project to the brain area stimulated (Windels et al.,2003), an effect that may result in neuronal depolarization (Hablitz &Langmoen, 1982; Sutor & Hablitz, 1989).

Experimental evidence supports HFS increase of γ-aminobutyricacid (GABA) release under normal (Luna-Munguía et al., 2012) and ep-ileptic conditions (Mantovani et al., 2006; Zhang et al., 2008). Augmen-tation of GABA in the synaptic cleft (Li et al., 2004) could result fromincreased recruitment of GABAergic fibers close to the target andGABAergic inputs from other brain regions (Windels et al., 2003), or in-hibition of pre-synaptic GABA transporters (GAT), resulting in the re-duced reuptake of this amino acid.

HFS induces a marked augmentation in the release of adenosine-5′-triphosphate (ATP), resulting in accumulation of its catabolicproduct, adenosine. This effect is more evident in cathodic stimulation(Bekar et al., 2008). The antiepileptogenic effect of DBS at low frequencyon kindling model might be mediated through activation of adenosineA1, but not A2A receptors (Mohammad-Zadeh et al., 2009). Controver-sial evidence exists concerning the role of histamine in DBS effects. Inter-mittent stimulation of the histaminergic tuberomammillary nucleus hasbeen found to be effective in desynchronizing electroencephalographic(EEG) activity in pentylenetetrazol-induced seizures (Nishida et al.,2007). In contrast, HFS of the histaminergic tuberomammillary nucleusin rats facilitates progression of amygdaloid kindling (Wu et al., 2008).These discrepancies can be explained because histamine may inducepro- or anticonvulsant effects, depending on the receptor activated(Lebois et al., 2011; Miyata et al., 2011; Walter & Stark, 2012).Concerning monoamines, serotonin rather than norepinephrine ordopamine, appears to be a selective neurotransmitter involved in medi-ation of HFS-induced inhibitory effects in the anterior thalamic nucleus,an effect associated with delay of pentylenetetrazol-induced seizures(Ziai et al., 2005; Mirski et al., 2009). With respect to opioid peptides,HFS of human thalamic nuclei induces a relative increase in met-enkephalin-like immunoreactivity in cerebrospinal fluid (Bourgoin etal., 1999). Concerning opioid receptors, autoradiography experimentsrevealed that the high effectiveness of HFS-induced antiepileptic effectsin patients with pharmacoresistant epilepsy correlates with lowermu, delta and nociceptin receptor binding, when compared with non-responsive patients (Rocha et al., 2007).

Several studies in animal models of PD support a potential neuro-protective effect of STN-DBS on dopaminergic neurons (Maesawa et al.,2004; Temel et al., 2006; Wallace et al., 2007; Harnack et al., 2008). Theconclusion that DBS is neuroprotective in parkinsonian animal modelswould suggest that this strategyholds potential to induceneuroprotectiveeffects in other neurological disorders such as pharmacoresistant epi-lepsy. However, this issue has not been investigated.


2.2. Vagal Nerve Stimulation and epilepsy

Vagal Nerve Stimulation (VNS) is the first non-pharmacological ad-junctive therapy approved by the European Community in 1994 and theFood andDrug Administration (FDA, U.S.) in 1997, applied for control ofpharmacoresistant epilepsy in patients in whom other therapeuticoptions, including surgery, have been exhausted. According to theAmerican Academy of Neurology, VNS is indicated for “adults and ado-lescents over 12 years of age with medically intractable partial seizureswho are not candidates for potentially curative surgical resections, suchas lesionectomies ormesial temporal lobectomies” (Fisher &Handforth,1999). VNS consists of chronic intermittent electrical stimulation of thevagus nerve, delivered by a programmable pulse generator. This pulsegenerator is surgically implanted subcutaneously in the chest wall andconnected to a bipolar electrode that is wrapped around the vagusnerve in the neck.

VNS dates back to the uncontrolled observations of James LeonardCorning in the late 19th century. Corning developed a series of instru-ments for the treatment of epilepsy based on the theory by HillierParry (1792) that epileptic seizures and headaches were disorders at-tributable to excessive cerebral blood flow. Corning observed thatdigital compression of the carotid artery induced a suppressive effecton epileptic seizures. Later, he combined arterial compression withtranscutaneous application of direct current to the vagus nerve andcervical sympathetic nerves. Despite the elicited adverse effect, in-cluding facial pallor, bradycardia, dizziness, and syncope, Corningconcluded that electrical stimulation was of great therapeutic valuein epilepsy (Lanska, 2002).

While it was evident that mechanical stimulation or compressionof the vagus nerve exerted an influence on the epileptic process, itwas not until the 1950s and 1970s that experimental evidenceshowed decreased epileptiform activity induced by strychnine inthe cerebral cortex of cats as consequence of VNS (Zanchetti et al.,1952; Stoica & Tudor, 1967). In 1985, Jacob Zabara suggested thatVNS was effective in preventing epileptic seizures in patients withpharmacoresistant epilepsy (Zabara, 1985). In 1988, the first devicesfor VNS were implanted as part of a pilot, single-blind trial of patientswith refractory partial seizures who were not candidates for epilepsysurgery (Penry & Dean, 1990). Results showed that VNS reducedepileptic activity in 3 of 4 patients. Subsequently, multicenter studiesconfirmed the effectiveness of VNS as treatment for patients withrefractory partial seizures (Ben-Menachem et al., 1994; Handforthet al., 1998). The efficacy of VNS on seizure control has been shownin a number of studies, referring a seizure reduction of 28% to 85%(McLachlan, 1993; Ben-Menachem et al., 1999; Fisher & Handforth,1999; Parker et al., 1999; Boon et al., 2002), and has been increasinglyindicated worldwide for the treatment of a number of epilepsy types(Connor et al., 2012). Its indications and long-term effects in thetreatment of other neurologic disorders (i.e. depression) are stillunder evaluation (Rizvi et al., 2011).

Several studies in acute and chronic experimental animal models ofepilepsy have evaluated the effect of VNS on seizure activity (Lockard etal., 1990; Zabara, 1992; McLachlan., 1993; Dedeurwaerdere et al., 2006;Aalbers et al., 2011). Results show that the effects of VNS on seizuresdepend on stimulation parameters, type of epilepsy and the experimen-tal model used (Aalbers et al., 2011). VNS has been suggested as astrategy to prevent epileptogenesis because it delays the developmentof amygdaloid kindling when applied before each kindling stimulus(Magdaleno-Madrigal et al., 2002). However, the antiepileptogeniceffects of VNS have not been reproduced by other authors(Dedeurwaerdere et al., 2006). It is important to notice that, althoughVNS is indicated in patients with refractory epilepsy, its efficacy hasbeen evaluated in only one study using pharmacoresistant animals(Muñana et al., 2002). In this study, a significant decrease in seizure fre-quency (34%) was detected during the final 4 weeks of VNS treatment(13 weeks total).

Desynchronization of cerebral electrical activity induced by VNS hasbeen proposed as a relevant mechanism to its anticonvulsant effect.The first study sustaining this notion was performed by Bailey andBremer (1938), who reported that VNS was able to modify EEG activityin the orbito-frontal cortex of cats. Using the encéphale isolé preparationin cats, Zanchetti et al. (1952) described that VNS at frequencies of 50 Hzand current intensity of 0.1–2 V produced EEG desynchronization in thewaking and slow wave sleep states. Later, it was reported that VNS in-duced desynchronization of the cerebral cortex depending on the typeof vagal fibers activated (Chase et al., 1966, 1967; Chase & Nakamura,1968). However, subsequent studies in humans failed to find evidencefor EEG changes induced by VNS, despite its effects to reduce seizure in-tensity and frequency (Hammond et al., 1992a; Salinsky & Burchiel,1993). Other studies indicate that VNS produces a selective and pro-nounced increase in inhibition in themotor cortexwith no effects on ex-citability in patients with epilepsy (Di Lazzaro et al., 2004). It is possiblethat the effect of VNS on cerebral activity depends on numerous factorssuch as the time of application (Koo, 2001) or the type of fibers stimulat-ed (Zagon & Kemeny, 2000).

A structure identified in the anticonvulsant effect of VNS is thenucleus of the solitary tract (NTS). Electrical stimulation of the NTS re-duces the severity of limbic seizures (Walker et al., 1999) and delaysepileptogenesis in animal models (Magdaleno-Madrigal et al., 2002).NTS receives 95% of the vagal afferent fibers and is regulated by choliner-gic innervation. The NTS ascending projection toward the forebrain isthrough theparabrachial nucleus, the locus coeruleus, cerebellum, dorsalraphe nucleus, reticular formation, hypothalamus, thalamus, amygdalaand hippocampus, among other structures (Hopkins & Holstege, 1978;Ricardo & Koh, 1978; Kalia & Sullivan, 1982; Rutecki, 1990; Castle et al.,2005). The locus coeruleus has also been implicated in the circuitry nec-essary for the anticonvulsant effects of VNS, probably due to activation ofthe noradrenergic system (Krahl et al., 1998). Another possible mecha-nism involved in the anticonvulsant effect induced by VNS is activationof the reticular formation at the brain stem level. However, to date,there is great controversy relating to the anti- or pro-epileptic effect in-duced by stimulation of this brain area (Ito et al., 1980; Kryzhanovskiĭet al., 1980; Chiu & Burnham, 1982; Browning, 1985).

Neurotransmitters that may play a role in the anticonvulsant ef-fect of VNS include norepinephrine (Krahl et al., 1998; Hassert et al.,2004; Roosevelt et al., 2006; Follesa et al., 2007; Raedt et al., 2011),epinephrine (Krahl et al., 2000), serotonin, dopamine (Hammond etal., 1992b) and GABA (Ben-Menachem et al., 1995; Walker et al.,1999). When applied subsequent to brain lesions, VNS protects corti-cal glutamic acid decarboxylase (GAD) positive neurons from death,and may increase GAD cell count in the hippocampal hilus (Neese etal., 2007). Using a single-photon emission computed tomography(SPECT) study in patients with pharmacoresistant epilepsy, it was de-scribed that VNS may modulate excitability of brain areas associatedwith epileptogenesis and that GABAA receptor plasticity contributesto this effect (Marrosu et al., 2003).

VNS has been proposed as a neuroimmunomodulatory strategy be-cause activation of afferent vagal fibers by endotoxins, cytokines or elec-trical stimulation can induce production of IL-1β in the hippocampus,cortex and hypothalamus and stimulates hypothalamic–pituitary–adrenal anti-inflammatory responses, whereas direct electrical stimu-lation of the peripheral vagus nerve in vivo during lethal endotoxaemiain rats inhibits the TumorNecrosis Factor (TNF) synthesis in liver, atten-uates the peak serum TNF amounts, and prevents the development ofshock (Borovikova et al., 2000; Hosoi et al., 2000; De Herdt et al.,2009a, 2009b).

2.3. Transcranial Magnetic Stimulation and epilepsy

The effects of magnetic field stimulation have been known for manyyears. In 1896, D'Arsonval in France showed the effects of a magneticfield on the human brain for the first time (D'Arsonval, 1896). In 1910,


the English electrical engineer, Silvanus P. Thompson attempted brainstimulation with magnetic fields (Thompson, 1910). He conducted ex-periments on himself, and described magnetophosphenes. However, itwas not until 1985, that the first clinical magnetic stimulators madetheir appearance.

Magnetic stimulation consists of awire coil throughwhich a pulse ofcurrent is passed. The pulse of current generates amagnetic field, whichpasses into the tissue and induces currents in the body. If currents are ofthe right amplitude and duration and have the right geometrical orien-tation related to the nervous tissue, they stimulate it by electrical mem-brane depolarization mechanisms. Transcranial Magnetic Stimulation(TMS), as the name implies, is a noninvasive technique that stimulatesa region of the brain by means of a rapidly cycling magnetic field. Apulse generator creates a high current (5000 A or more) for a brief pe-riod (in the order of milliseconds) that is passed through a coil placedon the scalp.

TMS has significant advantages over other brain stimulation strate-gies. One such advantage is that it is non-invasive and non-contacting.It is able to penetrate bone structures, but is not attenuated by thepresence of the skull, in spite of its high electrical resistance. However,magneticfieldsmay induce adverse effects including seizures, cognitionimpairment, mood changes, pain resulting from stimulation of periph-eral nerve terminals or local muscle contraction, and headache(Griskova et al., 2006).

TMS can modify seizure activity in both, human and experimentalmodels. In patients with pharmacoresistant epilepsy, TMS has been de-scribed to induce anti- or proconvulsant effects depending on the pa-rameters of application (Lisanby et al., 2000; Wassermann & Lisanby,2001). Concerning pharmacoresistant epilepsy, low frequency repeti-tive TMS (rTMS) has a favorable effect on seizure reduction, particularlyevident in patients with neocortical epilepsy or cortical dysplasia, andcan improve their psychological performance (Hsu et al., 2011; Sun etal., 2011).With respect to proconvulsant effects, literature reviews indi-cate that the risk of seizure in patientswith epilepsy undergoing rTMS issmall, and the risk of other mild adverse events is comparable to thatseen when rTMS is used to treat other diseases, which supports the no-tion that this type of stimulation may offer potential benefit with ac-ceptable negative consequences (Bae et al., 2007; Kimiskidis, 2010). Inexperimental models, magnetic field stimulation prolongs seizure la-tency (Juutilainen et al., 1988), induces a weak retardation in the kin-dling development (Ossenkopp & Cain, 1988), raises the seizurethreshold for kindled seizures (Potschka et al., 1998), and decreases fre-quency and mortality of seizures induced by pentylenetetrazol in rats(Ossenkopp & Cain, 1991). rTMS used to acutely reduce epileptic activ-ity correlates with a reduction in focal blood perfusion and clinical orEEG improvement (Graff-Guerrero et al., 2004). Other studies indicatethat therapeutic rTMS seems to influence distinct cortical regions, af-fecting regional cerebral glucose uptake rate (rCMRGlu) and regionalcerebral blood flow, effects that are region dependent and illness relat-ed (Conca et al., 2002).

Magnetic stimulation produces electrical currents that flow onlyparallel to the surface of the skull. Accordingly, under normal conditionsmagnetic stimulation will fail to stimulate pyramidal neurons in theneocortex directly, but might instead activate other neurons withaxons that run parallel to the surface of the cortex and excite pyramidalneurons trans-synaptically (Day et al., 1989; Amassian et al., 1990;Rothwell et al., 1991; Rothwell, 1994). However, cells are easier to acti-vate if the cortex is excitable (epilepsy), and more difficult to activate ifthe cortex is inhibited. Thus, responses to magnetic stimulation verymuch reflect the excitability of the cortex itself (Ridding & Rothwell,1997).

The physiologic basis of rTMS-effects has been associated withchanges in synaptic plasticity (Hoogendam et al., 2010). In animals,during direct cortical stimulation cortical neurons are depolarized at asubthreshold level, while they are hyperpolarized by cathodal stimuli(Purpura & McMurtry, 1965). Short trains of high-frequency

suprathreshold rTMS elicit a progressive increase in maximal evokedpotential size during and for a few hundred milliseconds after stimula-tion ends (short-term plasticity) (Pascual-Leone et al., 1994; Jennum etal., 1995; Ziemann et al., 2008). rTMS also enhances the synaptic effi-ciency expressed as the long-term potentiation (LTP) in both, humansand animals exposed to this type of stimulation (Siebner & Rothwell,2003; Ahmed & Wieraszko, 2006; Ziemann et al., 2008).

Under specific experimental conditions, TMS stimulation induces ex-citatory effects involving N-Methyl-D-aspartic acid (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainatereceptors (Ambriz-Tututi et al., 2012). rTMS on rat brains increasesNMDA binding sites in the ventromedial hypothalamus, the basolateralamygdala and layers V–VI of the parietal cortex (Kole et al., 1999). Theapplication of extremely low frequency (60 Hz) magnetic fields inten-sifies the convulsions induced by bicuculline, an effect associated withdecreased GABA levels in cortex, hippocampus and hypothalamus(Jeong et al., 2005). The same type of magnetic field stimulation doesnot modify seizures, but increase levels of glutamate and decreaseGABA in the picrotoxin-induced convulsions model (Sung et al., 2003).These studies suggest excitatory effects induced by magnetic fieldsunder specific experimental conditions such as the polarity of stimula-tion (Nitsche et al., 2003).

rTMS applied to rat brains induces up-regulation and down-regulation of β-adrenergic receptors in the frontal cortex and striatumrespectively; and down-regulation of 5-HT2 receptors in the frontal cor-tex (Ben-Shachar et al., 1997). Single rapid-rTMS exposure increasesthe number of 5-HT1A binding sites in the frontal cortex, the cingulatecortex, and the anterior olfactory nucleus (Kole et al., 1999; Keck etal., 2002). TMS also induces an enhancement of serotonin in hippocam-pus (Ben-Shachar et al., 1997), and extracellular dopamine in the dorsalhippocampus, the shell of the nucleus accumbens and the dorsal stria-tum (Keck et al., 2000; Kanno et al., 2004). The increase in dopamine as-sociated with enhanced glutamate release in nucleus accumbens(Zangen & Hyodo, 2002) may play a role in the antidepressant effectof TMS. rTMS augments the ATP content andMAP-2 expression after ce-rebral damage (Feng et al., 2008).

Magnetic fields can alter the effects induced by melatonin (Daviset al., 2001, 2006; Levallois et al., 2001; Swerdlow et al., 2006), an en-dogenous antiepileptic and neuroprotective compound (Giusti et al.,1997; Lima et al., 2011; Goldberg-Stern et al., 2012). This change ap-pears to be induced by uncoupling of melatonin-mediated inhibitorypathways, specifically, from melatonin receptors to adenylyl cyclase(Ishido et al., 2001). However, the effects of magnetic fields on mela-tonin seem to depend on parameters such as direction or polarizationand the time course of intensity of the magnetic fields, as well as ageand health status of the subject (Vanderstraeten et al., 2012).

No data exists concerning activation of opioid peptides by TMS inpatients with epilepsy. However, rTMS induces analgesia, an effectthat requires opioid activity (de Andrade et al., 2011; Taylor et al.,2012), and exposure to electromagnetic fields substantially potenti-ates morphine-induced place preferences in rodents (Lei et al.,2005). Contradictory results indicate that exposure to magnetic stim-uli may block morphine-induced analgesia and behavioral activity inmice, in a manner compatible and consistent with effects on Ca2+

(Kavaliers & Ossenkopp, 1986). Different results may be attributableto differences in experimental designs and/or rTMS parameters.

In brain lesions and pharmacoresistant epilepsy, apoptosis is themajor process of progressive cell loss through regulation of the Bcl-2(anti-apoptosis)/Bax (pro-apoptosis) ratio (Henshall et al., 2000;Uysal et al., 2003; Hu et al., 2004). High-frequency rTMS has beenreported to induce neuroprotection in experimental models of cerebralischemia (Fujiki et al., 2003; Ogiue-Ikeda et al., 2005), an effect associat-ed with an anti-apoptotic mechanism (increased Bcl-2 and decreasedBax expression) (Yoon et al., 2011). Since the anti-apoptotic proteinBcl-2 is known to improve neuronal survival following variousinsults and to be protective (Zhao et al., 2003; Abas et al., 2010), its


overexpression induced by rTMS application in patients withpharmacoresistant epilepsy can represent a therapeutic strategy to re-duce neuronal death.

3. Electrical modulation of the brain andpharmacotherapy: current evidence and futurepotential to control pharmacoresistant epilepsy

In general, patients with pharmacoresistant epilepsy have a longhistory of frequent seizures that resist pharmacological treatments,leading to an impaired quality of life. The clinical use of electricalmodulation of the brain is justified for medically refractory epilepsywhen patients are not candidates for resective brain surgery or thisstrategy has been failed to reduce seizure activity. The different strat-egies for electrical modulation of the brain appear to be safe and welltolerated, while its effectiveness is variable. It should be noted,however, that some procedures to induce electrical modulation ofthe brain are still considered an experimental strategy for epilepsy(Halpern et al., 2008).

When electrical modulation of the brain is applied, it is combinedwith AEDs to get good seizure control. Concerning this issue, it is impor-tant to consider the mechanisms of action of electrical modulation ofthe brain with the main purpose of an overall greater efficacy of AEDs,or vice versa. Another important issue is that drug resistance in epilepsyis a complex phenomenon that involves many mechanisms, few ofwhich arewell known. The following sections focus on the potential ad-vantages of combining electrical modulation of the brainwith AEDs andother strategies, according to themechanisms underlying the inhibitoryeffects, especially in pharmacoresistant epilepsy.

3.1. Electrical modulation of the brain and GABAergic neurotransmission

Studies indicate that DBS and VNS augment GABA neurotransmis-sion (Ben-Menachem et al., 1995; Lopez-Meraz et al., 2004) a situationthat could, in part, sustain a pronounced after-hyperpolarization and re-striction of interictal spike propagation (Windels et al., 2003) and

Fig. 1. Schematic illustration of different mechanisms of action at which interventional straThese include the administration of antiepileptic drugs which are not P-glycoprotein indGABAergic inhibitory neurotransmission, reduced excitatory glutamatergic neurotransmissthese augmenting the inhibitory effects of EMB (black arrows); and Na+ channel blockade

induce anti-anxiety effects (Adamec, 1999; Adamec & Young, 2000).Concerning pharmacoresistant epilepsy, experimental findings indicatethat HFS of neocortical slices obtained from patients induces the actionpotential-mediated release of GABA (Feuerstein et al., 2011). Patientswith pharmacoresistant epilepsy in whom HFS-induced antiepilepticeffect demonstrate enhanced GABA tissue content in parahippocampus,the brain area where the stimulation was applied. In contrast, HFS didnot modify epileptic activity when applied to the parahippocampus ofpatients with severe pharmacoresistant epilepsy associated to lowGABA tissue content (Cuellar-Herrera et al., 2004).

The antiepileptic effects induced by HFS in lithium-pilocarpine in-duced status epilepticus are augmented when it is combined withsub-effective doses of diazepam or phenobarbital (Cuellar-Herrera etal., 2010), both known as AEDs that increase GABAergic neurotransmis-sion (Haefely et al., 1975; Twyman et al., 1989; Barker and McBurney(1979)). Although these studies led to the suggestion that AEDsaugmenting GABAergic neurotransmission may improve the effectsinduced by DBS (Fig. 1), it results relevant to consider the status GABAsystem in pharmacoresistant epilepsy. The epileptic focus of subjectswithpharmacoresistant epilepsy presents alterations inGABAA receptors(Volk et al., 2006; Bethmann et al., 2008; Galanopoulou, 2010) and lowGABA interictal extracellular levels (During & Spencer, 1993; Cavus etal., 2005). Phenytoin-resistant kindled animals do not show significantchanges in GABA release secondary to HFS to the ventral hippocampus,in spite of the reduction in seizure susceptibility (Luna-Munguia et al.,2011). On the other hand, studies indicate that AEDs do not change3H-GABA release in neocortical synaptosomes obtained from patientswith pharmacoresistant epilepsy (Kammerer et al., 2011). Indeed, in ce-rebral tissue obtained from patients with pharmacoresistant epilepsy itwas found that GABA can have a depolarizing, i.e., excitatory and evenproconvulsive effect through GABAA receptors (Cohen et al., 2002),depending on intracellular ion concentrations (Staley & Proctor, 1999).It is possible that the participation of GABA-induced inhibitory or excit-atory neurotransmission in the effects produced by electricalmodulationof the brain may depend on specific conditions associated with thepharmacoresistance. Future studies using experimental models ofpharmacoresistant epilepsy should be carried out to evaluate the effects

tegies may modify the effects of electrical modulation of the brain (EMB) in epilepsy.ucers to avoid the effects of overexpression of efflux transporters; enhancement ofion, Ca2+ channel blockade and increased adenosine-induced inhibitory effects, all ofthat may restrict or even abolish the effectiveness of EMB (open arrow).


of electrical modulation of the brain combined with different GABAergicAEDs.

3.2. Electrical modulation of thebrain and glutamatergic neurotransmission

Increased glutamatergic neurotransmission has been proposed to berelevant for the DBS (Lee et al., 2004) and TMS effects (Ambriz-Tututi etal., 2012). Interestingly, VNS attenuates ischemia-induced glutamaterelease in the hippocampus (Miyamoto et al., 2003), whereas chronicVNS in epileptic patients decreases excitatory amino acids such as glu-tamate and aspartate in cerebrospinal fluid (Ben-Menachem et al.,1995).

It is possible that excitatory amino acid antagonists may improvethe antiepileptic effects induced by VNS, TMS and DBS in patientswith pharmacoresistant epilepsy in whom excessive release of gluta-mate during seizure activity is widely regarded as an important factorin the pathogenesis of epilepsy (During & Spencer, 1993; Cavus et al.,2005). Some AEDs interacting with glutamate receptors, such asfelbamate and valproate on NMDA receptors; and phenobarbital andtopiramate on AMPA receptors (Czuczwar, 2005) could be good can-didates to be combined with DBS and probably, VNS (Fig. 1).

However, it is important to consider that pharmacological modula-tion using glutamate antagonists in patients with intractable epilepsycould reduce long-term neuroplastic changes mediated by NMDA re-ceptors (Bennett, 2000). Thus, additional animal and human experi-ments should be performed to refute this idea.

3.3. Electrical modulation of thebrain and adenosinergic neurotransmission

It is known that adenosine induces anti-seizure effects in experimen-tal models of epilepsy (Van Dycke et al., 2010), and contributes to termi-nation of ongoing seizure activity (Whitcomb et al., 1990). Activation ofcentral adenosine A1 receptors leads to suppression of seizure activity ina mouse model of drug-resistant epilepsy (Gouder et al., 2003), whereasin patients with pharmacoresistant mesial temporal lobe epilepsy (TLE),the epileptic condition has been associated with the loss of anticonvul-sant A1 receptors (Glass et al., 1996) and dysregulation of adenosine ki-nase, the key metabolic enzyme in astrocytes regulating extracellularadenosine levels in the brain (Aronica et al., 2011).

Several studies indicate that HFS and rTMS activate adenosinergicsystems (Bekar et al., 2008; Feng et al., 2008; Mohammad-Zadeh etal., 2009). Association of HFS or TMS with A1 receptor agonists orwith a ketogenic diet, whose antiepileptic effects have been associatedwith decreased expression of adenosine kinase and subsequent facilita-tion of the adenosine-induced inhibitory effects through A1 receptors(Masino et al., 2011), could represent a good strategy to reduce seizureactivity in pharmacoresistant epilepsy (Fig. 1). However, it is relevant toconsider that high concentrations of extracellular adenosinemay aggra-vate epileptogenesis by activating the A2 receptors (Longo et al., 1995).

3.4. Electrical modulation of the brain and Na+ channel blockade

Voltage-gated Na+ channels represent major targets of severalfirst-line AEDs including carbamazepine, phenytoin, lamotrigine andvalproate (Ragsdale & Avoli, 1998; Köhling, 2000). Because use-dependent blockage of Na+ channels causes a preferential reduction ofNa+ channel availability during high- but not low-frequency firing, thismechanism is thought to be a key factor in the epileptiform inhibitionpotency of these anticonvulsants (Julien & Hollister, 1975; Yaari et al.,1986).

HFS combined with Na+ channel-blocking AEDs is ineffective in pa-tients with pharmacoresistant epilepsy (Velasco et al., personal com-munication). In the status epilepticus induced by litio-pilocarpine,sub-effective dose of phenytoin blocks the inhibitory effects induced

by HFS, a situation that results in a higher percentage of animalspresenting severe generalized seizures (Cuellar-Herrera et al., 2010).These effects can be explained because at therapeutic concentrations,the anticonvulsant efficacy of AEDs blocking voltage-dependent Na+

channels such as phenytoin results, at least in part, in limitation ofsustained high frequency repetitive firing (McLean & MacDonald,1983). Thus, these AEDs may block the neuronal activity pattern in-duced by HFS (Garcia et al., 2003) and prevent its protective effects. An-other explanation is that HFS seems to require a low transmembranesodium gradient to exert its effects on GABA outflow (Li et al., 2004;Mantovani et al., 2006). According to this information, blockage ofvoltage gated Na+ channels induced by phenytoin or other AEDs mayrestrict or even abolish the effectiveness of HFS on GABA outflow andaugment HFS-induced excitatory effects such as activation ofglutamatergic terminals (Zhang et al., 2008) (Fig. 1).

Concerningmagnetic stimulation, blockage of voltage-gated sodiumchannels by lamotrigine depresses paired associative TMS-inducedLTP-like plasticity (Heidegger et al., 2010). Although these studies indi-cate that Na+ channel blockers do not represent good candidates to becombined with TMS or HFS, additional experiments are necessary toconfirm this idea. In addition, it is relevant to consider that some pa-tients with pharmacoresistant epilepsy present resistance to AEDsblocking voltage-dependent Na+ channels (Remy et al., 2003; Jandováet al., 2006), a situation associated with alterations in the subunit com-position and expression of these channels (Bartolomei et al., 1997;Aronica et al., 2001; Whitaker et al., 2001; Ellerkmann et al., 2003)and reduced channel sensitivity to voltage- and frequency dependentinhibition by AEDs (Schaub et al., 2007), due to alterations in channelgating (Lucas et al., 2005).

3.5. Electrical modulation of the brain and Ca2+ channel blockade

Ca2+ plays an important role in regulating a great variety of neuronalprocesses. Like other cells, neurons use both extracellular and intracellu-lar sources of Ca2+. The outside entry of Ca2+ is regulated byreceptor-operated channels controlled by ionotropic neurotransmittersor voltage-dependent Ca2+ channels (VDCCs), that represent a majorclass of plasmamembrane channels throughwhich a significant amountof extracellular Ca2+ can enter neuronal cells (Berridge, 1998). Severalstudies have indicated changes in the dynamics of intracellular Ca2+ inepilepsy, i.e. altered intracellular Ca2+ buffering (Baimbridge et al.,1985; Köhr & Mody, 1991; Sloviter et al., 1991; Magloczky et al., 1997)in addition to altered Ca2+ entry through VDCCs (Vreugdenhil &Wadman, 1994) and AMPA receptors (Kamphuis et al., 1994). The hip-pocampus of patients with pharmacoresistant TLE shows alterations inthe distribution of VDCC β subunits (Lie et al., 1999), a situation thatmay contribute to TLE hyperexcitability.

Blockage of Ca2+ voltage-gated currents is considered as a mecha-nism by which HFS induces interruption of spontaneous neural activi-ties (Beurrier et al., 2001). Studies in rats indicate that combination ofHFS with sub-effective doses of Gabapentin, a drug that blocks theα2δ-Ca2+ subunit of voltage gated calcium channels and reduces Ca2+

currents (Gee et al., 1996), results in enhanced latency to statusepilepticus and reduces the incidence of severe generalized seizuresandmortality rate induced by pilocarpine (Cuellar-Herrera et al., 2010).

Magnetic fieldsmodify Ca2+ channel function in two differentways:a) by reducing permeability of voltage-gated Ca2+ channels, leading toa decrease in neurotransmitter release; and b) by facilitating the effluxof Ca2+ through channels regulating the accumulation of Ca2+ in the in-ternal stores (Wieraszko, 2000). High intracellular Ca2+ levels occurconcomitantly with increased activities of Ca2+-dependent proteinkinase-C (PKC), cAMP-dependent protein kinase and calcineurin aswell as decreased activity of Ca2+-calmodulin-dependent protein ki-nase. These effects are associated with decreased binding to NMDA re-ceptors (Manikonda et al., 2007) as well as long-lasting modulation ofsynaptic plasticity (Muller et al., 1991).


These studies indicate that modulation of Ca2+ channel function isrelevant to the inhibitory effects of electrical modulation of the brain.Future studies should be designed to identify the specific effects ofneuromodulation strategies combined with Ca2+ channel blockers,such as levetiracetam (Reis et al., 2004) (Fig. 1), in experimentalmodels of pharmacoresistant epilepsy, to evaluate possible undesir-able effects on the mechanisms of long-term synaptic plasticity asso-ciated with Ca2+ homeostasis (Ben-Ari et al., 1992).

3.6. Electrical modulation of thebrain and overexpression of drug efflux transporters

One theory explaining pharmacoresistant epilepsy involves cerebraloverexpression of the drug efflux transporters leading to poor absorp-tion of many AEDs (Aronica et al., 2011). At present, resistance mecha-nisms that involve P-glycoprotein (Pgp) overexpression are among themost intensively studied to explain pharmacoresistant epilepsy(Löscher & Potschka, 2002). Pgp was initially discovered in Chinesehamster ovary cells selected for resistance to colchicine, and itwas asso-ciated with control drug permeation by modulating the properties ofhydrophobic membrane regions (Juliano & Ling, 1976). Pgp, a phos-phorylated glycoprotein of 170,000 Da apparent molecular weight, isa product of the ABCB1 (also known as the multidrug resistance 1(MDR1)) gene that limits the absorption of orally administered drugs,promotes drug elimination into bile and urine, and protects various tis-sues (e.g. brain, testis and fetus) from potentially toxic xenobiotics(Fromm, 2004). Pgp localized in the luminal (apical) membrane ofbrain capillary endothelial cells, represents a general defense mecha-nism in the mammalian BBB avoiding diffusion of harmful lipophiliccompounds into the brain parenchyma (Schinkel et al., 1996, 1997).At the neuronal level, expression of Pgp has been associated with alowmembrane potential (Wadkins & Roepe, 1997; Roepe, 2000), lead-ing to an increased sensitivity to seizure activity induction (Lazarowskiet al., 2007).

Pgp overexpression in brain capillary endothelial cells and its abnor-mal expression in astrocytes and neurons is a common feature inpharmacoresistant epilepsy (Lazarowski et al., 1999, 2004, 2007;Löscher & Potschka, 2002; Sisodiya et al., 2002; Sisodiya, 2003;Aronica et al., 2004; Volk & Löscher, 2005). Various AEDs are substrates

Fig. 2. A) Schematic illustration of the blood–brain barrier (BBB) overexpressing drug effluxsion of antiepileptic drugs (AEDs) from the brain. Arrows indicate the proposed directionrepresentation of the hypothetical downregulation of Pgp induced by electrical modulationelectrical stimulation, and Hirata et al. (2001) and Kuo and Lu (2012a, 2012b) using electrothe brain of AEDs.

for Pgp, and the overexpression of such efflux pump in the BBB reducespenetration into the brain, an effect avoided when Pgp blockers are ad-ministered (Löscher & Potschka, 2002; Potschka et al., 2004; Volk &Löscher, 2005). Glutamate, which is excessively concentrated in the ex-tracellular space during ictal and interictal periods (During & Spencer,1993; Wilson et al., 1996; Cavus et al., 2005; Luna-Munguia et al.,2011), is critically involved in seizure-induced overexpression of Pgpvia a glutamate/cyclooxygenase-2 mediated signaling pathway (Zhu &Liu, 2004; Bankstahl et al., 2008; Bauer et al., 2008; van Vliet et al.,2010). According to this information, blocking several interestingtargets, including the NMDA receptor, the inflammatory enzymecyclooxygenase-2, and the prostaglandin E2 EP1 receptor can controlPgp expression, improve antiepileptic drug brain-penetration, andhelp overcome pharmacoresistance (Potschka, 2010). In this context,Pgp antagonism has been suggested as a therapeutic target for over-coming transporter-mediated pharmacoresistance (Robey et al., 2008;Iannetti et al., 2009).

Experiments using tumor cells show that electrical stimulation at50 Hz decreases Pgp expression and its drug extrusion potency, to agreater extent than that achieved by tariquidar, a Pgp inhibitor, at theEC50 level (Janigro et al., 2006). Similarly, electromagnetic fields couldeffectively inhibit expression and function of Pgp and multidrugresistance-associated protein (MRP1) and enhance delivery of Pgp sub-strates across the BBB (Hirata et al., 2001; Kuo & Lu, 2012a, 2012b). It ispossible that electrical modulation of the brain may decrease Pgp ex-pression and function through a subsequent enhancement of themem-brane electrical potential (Fig. 2).

At therapeutic doses, some AEDs act as inducers of efflux trans-porters (Moerman et al., 2011), whereas low concentrations of the in-ducing agent may return the transporter expression to baseline values(Maldonado et al., personal communication). Then, the combinationof TMS or DBS with subeffective doses of specific AEDs appears to bean interesting strategy to produce an effective antiepileptic effect inpatients with pharmacoresistant epilepsy. An ideal adjunctive treat-ment of DBS or TMS could be the association of low doses of an AEDworking against almost every type of epilepsy and that is not an effluxtransporter inducer, such as valproic acid (Moerman et al., 2011)(Fig. 1). Additional research is necessary to identify possible disadvan-tages induced by TMS or DBS such as the entrance into the brain of

transporters (Pgp) characteristic of pharmacoresistant epilepsy, enhancing the extru-of transport (based on Aronica et al., 2011; Löscher & Potschka, 2002). B) Schematicof the brain (EMB) according with the results obtained by Janigro et al. (2006) applyingmagnetic fields. The downregulation of efflux transporters may allow the entrance into

image of Fig.�2


non-desirable substances as a consequence of the down-modulation ofefflux transporters.

4. Relevance of long lasting effectsinduced by electrical modulation of the brain

Although at present, long-term effects induced by electrical mod-ulation of the brain have been occasionally reported and not very wellstudied, they are relevant for the control of pharmacoresistant epilep-sy because they may allow reduction of the doses as well as the unde-sirable effects of AEDs.

The first observation of long-term effects induced by electrical mod-ulation of the brainwas obtained by Benabid et al. in 1987, who reportedthat reduced PD tremor and extra-pyramidal dyskinesias induced byHFSat 130 Hz to the ventral tegmental nucleus last from 2 to 14 months. Infully kindled animals, HFS applied to the ventral hippocampus increasesrefractoriness to subsequent seizures during the postictal period, an ef-fect detected 48 h after the last kindling stimulation (Cuellar-Herreraet al., 2006). Similarly, HFS applied to the substantia nigra pars reticulataof amygdala-kindled rats induces an antiepileptic effect that lasts up to4 days (Shi et al., 2006). Experiments in rats revealed that evenupon dis-continuation of VNS, animals show a reduction in the incidence and du-ration of seizures induced by pentylenetetrazol (Takaya et al., 1996).VNS, aswell as electrical stimulation of theNTS, induces a long-termpro-tective effect on kindling epileptogenesis (Fernández-Guardiola et al.,1999; Magdaleno-Madrigal et al., 2002). Stimulation of NTS during6 days prior to the initiation of the kindling process results in a preemp-tive effect on epileptogenesis, a situation associated with no progressiveincrease in afterdischarge duration (Magdaleno-Madrigal et al., 2010).VNS also induces long-term effects on the EEG and on different stagesof the sleep–wake cycle (Valdés-Cruz et al., 2008). VNS produces manybeneficial effects on clinical symptoms observed during the postictalstate, such as improved depression, a better postictal recovery period, re-duced amount of AEDs to terminate seizures, improved alertness, mem-ory and mood. Some of these effects are detected after six months oftreatment, in spite of no significant changes in seizure frequency insome patients (Vonck et al., 2010). Neurophysiological and neurologicalhuman studies have reported a modification of cortical excitability afterrTMS, which outlasts the stimulation period for 5–30 min andmay evenlead to longer-lasting potentially beneficial effects to treat neuropsychi-atric disorders (Feng et al., 2012). These responses seem to be influencedby stimulation train length and intensity (George et al., 2002; Fitzgeraldet al., 2006).

Gene expression modulation can be involved in long term effectsinduced by electrical modulation of the brain. Evaluation of gene ex-pression profiles in rat brain reveal that chronic HFS modulates the ex-pression of 176 genes, especially genes involved in proliferation andneurogenesis such as nestin and doublecortin, aswell as genes encodingproteins that may support neural differentiation or migration, such asTimp1, Ccl2, S100a4 and Angpt2 (Kádár et al., 2011). Acute rTMS ap-plied to the rat brain can substantially alter expression of immediateearly genes c-Fos and zif268, indicative of recent changes in electricalneuronal activity (Aydin-Abidin et al., 2008). Experiments on synapticplasticity indicate that zif268 expression is essential for induction andpersistence of LTP (Cole et al., 1989; Abraham et al., 1993), an effectthat has been found to be dependent on NMDA receptor activation(Wisden et al., 1990; Gass et al., 1993; Wang, 1998). On the otherhand, enhanced c-Fos expression induced by TMS (Aydin-Abidin et al.,2008) has been explained as a consequence of increased dopamine re-lease (Robertson et al., 1991; Hyman et al., 1995) and may be involvedin functional neurological recovery mechanisms (Zhang et al., 2007).

VNS and HFS induce increased expression of DeltaFosB, a biomarkerof long-term neuronal activity, in specific brain areas (Oueslati et al.,2007; Cunningham et al., 2008). The expression of DeltaFosB, which isa highly inducible process in the adult brain in response to various in-sults such as ischemic reperfusion injury, electrical stimulation induced

seizures or cocaine administration, has been involved inmechanisms ofneuroprotection and neurogenesis in response to brain damage (Miuraet al., 2005), aswell as in themolecular pathwayunderlying antidepres-sant responses (Vialou et al., 2010). It is possible that the enhanced ac-tivation of DeltaFosB induced by VNS and HFS participates in the longterm effects and postictal mood and cognition improvement in patientswith pharmacoresistant epilepsy (Furmaga et al., 2012).

Brain-derived neurotrophic factor (BDNF) is a neurotrophin highlyexpressed in hippocampus and cortex (Murakami et al., 2005) and im-plicated in neurogenesis, neuron survival, synaptic signaling, synapticconsolidation (Allen & Dawbarn, 2006) and memory formation(Cunha et al., 2010). Mature BDNF plays a key role in all stages of LTP,inducing dendritic and axonal growth and de novo gene expression(Bramham & Messaoudi, 2005). BDNF induces effects by activation ofthe receptor tropomyosin-related kinase B (TrkB) with high potencyand specificity (Massa et al., 2010). Indeed, TrkB activation plays an im-portant role in epileptogenesis (He et al., 2010; Heinrich et al., 2011).ERK1/2 are essential components of pathways through which signalsreceived at membrane receptors are transduced to specific changes inprotein function and gene expression (Chen et al., 2001; Pearson et al.,2001). ERK1/2 activation is also responsible for BDNF's effects onspine growth in hippocampal CA1 pyramidal neurons (Alonso et al.,2004). ERK1/2 activated in response to various physiological stimuliand pathological events such as brain ischemia and epilepsy (Pearsonet al., 2001; Otani et al., 2003; Merlo et al., 2004; Di Maio et al., 2011),has been proposed to induce neuroprotective effects (Qiao et al., 2012).

The up-regulation of BDNF secondary to HFS, VNS or TMS (Mulleret al., 2000; Follesa et al., 2007; Zhang et al., 2007; Spieles-Engemannet al., 2011; Hoyer et al., 2012) may exert pronounced and underap-preciated changes on plasticity that may play a role in the symptom-atic effects of this therapy. However, it is important to consider that,in contrast to patients with TLE without hippocampal sclerosis,BDNF transcripts are selectively upregulated in patients with TLEand hippocampal sclerosis inducing excitability of dentate granulecells (Wang et al., 2011). It is possible that the mechanisms bywhich BDNF influences plasticity in epilepsy may depend on severalfactors such as duration of epilepsy and the rate of cell damage. Addi-tional studies would be necessary to devise BDNF-based therapeuticsfor human pharmacoresistant epilepsy.

5. Neurogenesis and electrical modulation of the brain

Neurogenesis in the adult brain may play a key role in learningand memory (Snyder et al., 2001; Shors, 2004). Augmentation ofneurogenesis and migration of newly born neurons into ectopic re-gions such as the hilus and the molecular layer of the dentate gyrusare seen after acute seizures, status epilepticus, or head injury andplay a role in the occurrence of epileptogenic hippocampal circuitry(Kuruba et al., 2009). In contrast, decreased density of PSA-NCAM(a putative marker of newly born neurons) positive cells in the dentategyrus from pediatric patients with frequent spontaneous seizures(Mathern et al., 2002) and adult patients with pharmacoresistant TLEhas been demonstrated (Pirttilä et al., 2005). These and other evidence(Crespel et al., 2005; Fahrner et al., 2007) support the notion thatpharmacoresistant epilepsy is associated with decreased hippocampalneurogenesis, a situation that might contribute to the persistence ofspontaneous seizures, depression, learning and memory impairments(Kuruba et al., 2009; Paradisi et al., 2010).

Additional studies indicate that VNS, HFS and TMS facilitate process-es associated with neurogenesis. Ueyama et al. (2011) detected en-hanced neurogenesis in the dentate gyrus of rats treated with rTMSfor 14 consecutive days. It is known that chronic and acute VNS inducepersistent changes in hippocampal neurogenesis, an effect associatedwith increases in the amount of BDNF immunoreactivity and the num-ber of BDNF+ cells aswell as in the dendritic complexity of neurons ex-pressing doublecortin (Biggio et al., 2009). Using mice, Encinas et al.


(2011) found that HFS to the anterior thalamic nucleus increased thenumber of new neurons, subsequent to increased symmetric divisionsof a defined class of neural progenitors in the dentate gyrus. Althoughno experimental evidence exists that electrical modulation of thebrain induces neurogenesis in humans, Cuellar-Herrera et al. (2004)found that patients with pharmacoresistant epilepsy who respondedto HFS, also showed a low rate of cell loss in the parahippocampal cor-tex. “Low cell loss” found by these authors could be explained as a con-sequence of HFS-induced neurogenesis. However, further studies areneeded to confirm this notion.

Potential mechanisms activated by electrical modulation ofthe brain underlying the increase in neurogenesis can be proposed:a) up-regulation of BDNF, a factor that promotes proliferation andsurvival of neurons; b) activation of the GABA system leading to apositive impact on proliferation of neural progenitors, migration anddifferentiation of neuroblasts, and synaptic integration of newbornneurons in the dentate gyrus a short time after a seizure (Ge et al.,2007); and c) release of ATP, considered an important small moleculefor the proliferation of rapidly dividing cells and Type C cells insubventricular zone (SVZ) (Suyama et al., 2012) (Fig. 3).

An important issue is that decreased neurogenesis, cognitive impair-ments and depression co-exist in chronic epilepsy (Hattiangady et al.,2004; Kanner, 2011; Badawy et al., 2012), while various chronic antide-pressant treatments increase adult hippocampal neurogenesis and ap-pear to be a useful approach to reduce these problems (Santarelli et al.,2003; Perera et al., 2007, 2008). These studies may support the hypoth-esis that enhanced neurogenesis in the hippocampus is essential for theeffective antidepressant effects of therapeutic strategies such as electricalmodulation of the brain (Anderson et al., 2012). To answer the questionofwhether or not neuromodulation-induced neurogenesis decreases thelikelihood of seizure activity, improves hippocampal-dependent learningand memory function and reduces depression in subjects withpharmacoresistant epilepsy, it is necessary to determine how the inte-gration of newly born cells into the existing neuronal network isachieved and how this integration contributes to network excitability.On the other hand, and considering that some antidepressant drugsalso induce anticonvulsant effects (Vermoesen et al., 2012), experimentsshould be carried out to determine if neuromodulations therapy com-bined with antidepressant drugs results in augmentation of the

Fig. 3. Schematic illustration showing potential mechanisms at which electrical modu-lation of the brain (EMB) may revert the reduced neurogenesis associated with chronicepilepsy. These mechanisms include up-regulation of Brain-Derived Neurotrophic Fac-tor (BDNF); activation of the GABAergic system leading to facilitation of proliferation ofneural progenitors, migration and differentiation of neuroblasts, and synaptic integra-tion of newborn neurons in the dentate gyrus a short time after a seizure (Ge et al.,2007); and release of ATP, a small molecule relevant for the proliferation of rapidly di-viding cells and Type C cells in subventricular zone (Suyama et al., 2012).

antiepileptic effects of both strategies and lowers comorbidity of depres-sion in patients with pharmacoresistant epilepsy.

6. Role of inherent severity of epilepsy and brain damageon the effects induced by electrical modulation of the brain

It is known that not all patients with pharmacoresistant epilepsy re-spond to electrical modulation of the brain. Patients with an etiology ofneuronal migration disorders or patients with multifocal or diffuse ac-tivity tend to respond less well to VNS, when compared with patientsexhibiting exclusively focal seizures or focal activity. Although no pur-ported markers for more severe epilepsy (duration of epilepsy, numberof seizure types, number of failed AEDs) anticipate a worse response toVNS therapy (Elliott et al., 2011), a younger age at initiation of treat-ment has been described to be a positive predictor (Ghaemi et al.,2010). With respect to DBS, studies carried out in patients with intrac-table epilepsy indicate that HFS induces more effective antiepilepticeffects in younger subjects with shorter seizure history, lower seizurefrequency and less incidence of mesial temporal sclerosis (Cuellar-Herrera et al., 2004). It is possible that an inherent high severity of sei-zure activity in some patients with drug resistance epilepsy (Rogawski& Johnson, 2008; Löscher & Brandt, 2010) participates in lower respon-siveness to neuromodulation therapy.

Another possibility is that brain is not a homogenous tissue and dif-ferent cerebral structures have different conductivities (Holsheimer,1987). Indeed, conductivity itself can vary as consequence of neuro-pathological alterations associated with pharmacoresistant epilepsy,such as mesial sclerosis as well as abnormal structural or biochemicalproperties of neurons adjacent to the sclerotic area (Babb et al., 1984).

Recent data demonstrates that astrocytesmay be active players in theDBS mechanism of action (Vedam-Mai et al., 2012). Astrocytes also playa major role in the removal of [K+]o through the inwardly rectifying po-tassium ion (Kir) channels (de Lanerolle et al., 2010), a mechanism im-paired in the epileptic tissue obtained from experimental models ofepilepsy (Gabriel et al., 1998) as well as in sclerotic hippocampi of pa-tients with TLE (Bordey & Sontheimer, 1998; Hinterkeuser et al., 2000).A defective Kir channel, particularly Kir4.1, has been proposed as themain mechanism to explain reduced extracellular potassium uptake byastrocytes in the sclerotic area (Jansen et al., 2005; Steinhäuser et al.,2012). The epilepsy-induced morphological and functional alterationsof astrocytes (Losi et al., 2012), reactive astrocytosis characterized bydef-icits in inhibitory synaptic transmission (Ortinski et al., 2010), anddownregulation of Kir channels may facilitate seizure activity (Kivi etal., 2000; De Lanerolle et al., 2010) and reduce the responsiveness toelectrical modulation of the brain (Fig. 4). Pharmacological strategies fo-cused to restore glial potassium buffering mechanisms (Gabriel et al.,1998) can represent a good strategy to improve the antiepileptic effectsinduced by electrical modulation of the brain.

Adenosine release from astrocytes (Zhang et al., 2003; Pascual etal., 2005) has been involved in the brain stimulation-induced modu-lation of neuronal responses and cessation of abnormal oscillatory ac-tivity during epilepsy (Tawfik et al., 2010). Clarifying the astrocyterole in the effects induced by electrical modulation of the brain inpharmacoresistant epilepsy could reveal adenosine release from as-trocytes as a novel therapeutic strategy.

Another important issue to be considered in future studies is that theeffects of electrical modulation of the brain depend on the pathologicalcondition of neural tissue. For example, HFS applied to the STN during5 days dramatically reduced spontaneous glutamatergic neural activityin 6-OHDA-lesioned rats, an effect associated with a significant im-provement in akinetic symptoms. Interestingly, DBS has no such effectsin sham animals, suggesting that dopamine loss might be necessary forSTNHFS to affect spike activity in striatal neurons (Gubellini et al., 2006,2009). On the other hand, neuroprotective effects may be producedwhen HFS is applied during earlier stages of PD (Hilker et al., 2005), anotion supported by studies carried out in experimental models

image of Fig.�3

Fig. 4. Schematic illustration of different changes associated with temporal lobe epilepsy that may lead to responsiveness or unresponsiveness to electrical modulation of the brain(EMB). Patients showing long duration of epilepsy and high seizure frequency, associated with mesial sclerosis and decreased function and expression of Kir channels are suggestedto present glial disfunction and lower efficacy of EMB to reduce seizure activity. In contrast, patients with shorter duration of epilepsy, reduced cell damage and normal expressionand function of Kir channels may present beneficial effects as consequence of EMB associated with normal glial function.


(Spieles-Engemann et al., 2010). This evidence suggests that electricalmodulation of the brain has the potential to delay the progressive dele-terious changes associated to disorders, such as PD and epilepsy, whenapplied in early stages of the disease.

7. Conclusions

Experimental data provide a good basis for the combination of elec-trical modulation of the brain with some AEDs and other therapeuticstrategies. It is evident from the data presented above that combinationof neuromodulation therapies with other therapeutic strategies is prom-ising to avoid epileptogenesis, induce neuroprotective effects, reduce sei-zure activity and control pharmacoresistant epilepsy (Fig. 5). Accordingto the information provided in this review, numerous mechanisms at

Fig. 5. Schematic illustration of various effects at different time-points at which electrical mavoid or alleviate epilepsy. These effects include a) antiepileptogenesis effect when appliedthe epileptogenesis process; c) anticonvulsant effect in subjects with chronic epilepsy; and

multiple levels are involved in the effects of electrical modulation ofthe brain. Selective agonists or antagonists may allow researchers toidentify the mechanisms of action in more detail and will provideadditional options to combine neuromodulatory strategies with specificdrugs.

The benefits of neuromodulation therapies combined with effectiveAEDs must be evaluated in conjunction with the risk of side effects. Forexample, vigabatrin, an AED for the treatment of refractory complexpartial seizures and infantile spasms is well-tolerated with an adverseevent profile (including drowsiness, dizziness, headache, fatigue, seda-tion, somnolence, and irritability) similar to that of other AEDs (Walker& Kälviäinen, 2011). However, enhanced GABAergic tone induced byvigabatrin might trigger a lowmotivational state, anhedonia and a pos-sible memorymechanism for unpleasant experiences (Skirzewski et al.,

odulation of the brain associated with other interventional strategies may be applied toat the onset of epileptogenesis process; b) neuroprotective effect when applied duringd) control of disease in subjects with pharmacoresistant epilepsy.

image of Fig.�4

image of Fig.�5


2011). Then, vigabatrin may restrict or even abolish the effectiveness ofelectrical modulation of the brain to induce antidepressant effects(Vonck et al., 2010).

There are a number of important limitations that must be kept inmind. First of all, most of the studies focused on the evaluation of themechanisms of action of electrical modulation of the brain have beencarried out in normal animals. The evaluation of neuromodulation ther-apies in experimental models of pharmacoresistant epilepsy is indis-pensable since this is a complex phenomenon that involves manymechanisms. A limited number of neurological centers through theworld can provide electrical modulation of the brain, and neurosur-geons who are interested in this strategy have to obtain specializedtraining throughmedical educational programs, including postgraduateclinical training and visiting scholar programs. Finally, the medical ex-pense of neuromodulation therapies is a heavy burden for the patients.It is important to assess not only the efficacy of novel neuromodulatoryinterventions associated with pharmacotherapy, but also their cost.Future studies should be designed to determine if an expensiveneuromodulation therapy associatedwith the proper pharmacotherapymay be far less expensive than other alternatives.

Multidisciplinary collaboration is needed to advance science towarddaily use of neuromodulation therapy alone and associated with othertherapeutic strategies to control pharmacoresistant epilepsy. The re-sults from experimental studies can only be extrapolated to the clinicalsetting with caution. Indeed, a considerable amount of experimentaldata should be in agreement with what is observed in patients withpharmacoresistant epilepsy.

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgments

The author acknowledges Ms. Leticia Neri Bazan and Mr. HectorVazquez Espinosa for their excellent technical assistance and Dr. ErikaBrust-Mascher for English improvement. The author's own work wassupported by a research grant from theMexican National Council of Sci-ence and Technology (CONACyT 98386).

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